Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin

Frontiers in Pharmacology

Nana Yaa Gyaama Owusu-Tieku¹  Chunhui Sun¹  Xiaoyong Dai¹  Laiqiang Huang¹  Hsiang-I Tsai³  Kewei Liu³  Hongbo Chen³  Fahim Ullah Khan³  Yanping Wu³ 

[1] Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, China;School of Life Sciences, Tsinghua University, Beijing, China;Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China;

关键词: fibromodulin (FMOD);    gene expression;    Wnt/β-catenin pathway;    cancer metastasis;    aspirin;    anti-cancer effects;   

DOI  :  10.3389/fphar.2019.01308

来源: DOAJ

【 摘 要 】

Emerging evidence suggests that fibromodulin (FMOD), an extracellular matrix protein, is associated with cancer, and yet little is known about the regulation of FMOD expression and its role in cancer metastasis. Aspirin, a classic anti-inflammatory drug, has been indicated to offer anticancer benefits, but its action targets and mechanisms remain obscure. In the present study using cell lines, animal model and database analysis, we show that FMOD is crucial for breast cancer cell migration and invasion (BCCMI) via activation of ERK; expression of FMOD is regulated positively by the Wnt/β-catenin pathway, wherein the β-catenin/TCF4/LEF1 complex binds the FMOD promoter to transcribe FMOD. Aspirin inhibits BCCMI by attenuating Wnt/β-catenin signaling and suppressing FMOD expression via inhibiting deacetylation of β-catenin by histone deacetylase 6 (HDAC6) leading to β-catenin phosphorylation and cytoplasmic degradation. Moreover, expression of the transcriptional complex components β-catenin/TCF4/LEF1 is upregulated by the Wnt/β-catenin pathway, constituting positive feedback loops that amplify its signal output. Our findings identify a critical role of FMOD in cancer metastasis, reveal a mechanism regulating FMOD transcription and impacting tumor metastasis, uncover action targets and mechanism for the anticancer activity of Aspirin, and expand the understanding of the Wnt/β-catenin pathway and tumor metastasis, which are valuable for development of cancer therapeutics.

【 授权许可】

Unknown